Brain stimulation therapies are currently used to treat several types of neurological disorders (Parkinson's disease, dystonia, eplilepsy) and hold promise for treatment of many others (Alzheimer's, anxiety, schizophrenia, and stroke, for example). Current clinical applications of brain stimulation involve either implanted electrodes (which is limited by the invasive nature of the implantation) or transcranial magnetic stimulation (limited by its spatial resolution and depth penetration). Recently, it was shown that focused ultrasound (a non-invasive technology capable of deep brain penetration) can activate voltage-gated sodium channels (Nav channels) and consequently increase the rate of action potential firing in the mouse motor cortex in vivo. These findings indicate that focused ultrasound could overcome the limitations of current brain stimulation therapies, thereby expanding the usefulness of brain stimulation and revolutionizing treatment of neurological disorders. However, the mechanisms by which focused ultrasound stimulates brain activity are not understood, causing a critical bottleneck in development of this technology. Knowledge of the mechanistic basis by which ultrasound activates the ion channels that generate brain activity will revolutionize the development of ultrasound as a tool for neurostimulation. To achieve such a mechanistic understanding, the interaction of ultrasound with membranes and ion channels will be studied using several carefully-controlled experimental systems: pure lipid bilayers, lipids bilayers with a model ion channel (gramicidin), and lipid bilayers with Nav channels. The use of model systems will allow us to determine the ultrasound parameters that ideally activate ion channels while minimizing undesired effects on membranes or membrane proteins, which would be an intractable task in the complex environment of an intact brain. Preliminary experiments reveal that model membranes devoid of proteins exhibit a robust electrical response to ultrasound stimulation and lead us to hypothesize that (1) ultrasonic radiation pressure subtly distorts lipid bilayer structure;(2) these distortions alter the equilibrium between functional states of membrane proteins through protein-bilayer interactions;and (3) these interactions are mediated by hydrophobic mismatch between protein and bilayer. The proposed experiments will test these hypotheses using electrophysiological recording and optical interferometry measurements in the three experimental systems. The results will provide a crucial and quantitative framework for developing focused ultrasound as a non-invasive tool for experimental and therapeutic deep brain stimulation. PUBLIC HEALTH RELEVANCE: Focused ultrasound is a promising new technology that can be used to stimulate brain activity and has the potential to provide revolutionary new therapies for numerous neurological disorders. However, the mechanisms by which focused ultrasound stimulates brain activity are not understood, causing a critical bottleneck in development of this technology. This research will provide the necessary mechanistic understanding of how focused ultrasound stimulates brain activity.